Blood : , Acute Myelogenous , and Chronic Lymphocytic Lymphoma Pamela Crilley, DO Hematologist/Medical Oncologist Chair, Department of Medical Treatment Centers of America

1 Faculty Disclosure

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2 Learning Objectives

. Discuss the presentation and diagnosis of blood cancers in adults . Describe the treatment options available for blood cancers in adults . Discuss outcomes and prognosis for blood cancers in adults

3 Outline:

• Diseases featured are: Lymphoma, Acute Myelogenous Leukemia, and Chronic Lymphocytic Lymphoma • Review presentations and diagnostic evaluation • Assess disease extent and treatment options • Outcomes and prognosis

4 HODGKIN’S LYMPHOMA

Thomas Hodgkin

5 INTRODUCTION

✤ 8000 cases annually, with slight male predominance

✤ Bimodal age distribution, with peak incidence at 15-30, and above 55 years

✤ EBV exposure and immunosuppression are RFs

✤ Treatment advances have made it a highly curable disease

✤ Focus is now shifting towards limiting toxicity of treatment

6 PRESENTATION

✤ Asymptomatic LAP

✤ (50% in advanced disease)

✤ Mediastinal mass

✤ Pruritus

✤ Pain at involved areas after alcohol (10%)

✤ Paraneoplastic: cholestasis, CNS, nephrotic syndrome, eosinophilia, AIHA, leukocytosis, thrombocytosis

7 WHO CLASSIFICATION

✤ CLASSICAL

- Nodular sclerosis CHL

- Mixed cellularity CHL

- Lymphocyte depleted CHL

- Lymphocyte rich CHL

✤ NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA

8 HL: DISTRIBUTION BY TYPE

✤ 95% of all HL is Classical HL: ✤ 70% Nodular Sclerosis ✤ 25% Mixed Cellularity ✤ 5% Lymphocyte rich ✤ 1% Lymphocyte depleted

✤ 5% of cases are Nodular Lymphocyte Predominant HL: – HRS cells (L&H cells) have B cell markers . CD 20 and surface Immunoglobulin . Negative for CD15 and 30

9 CLASSICAL HODGKIN LYMPHOMA

Reed Steinberg cells • Large bilobed nucleus • “owl’s eye” appearance

• Prominent eosinophilic inclusion like nucleoli

• CD 30 and 15 positive

• CD 20 and 45 negative (in most cases)

10 HODGKIN LYMPHOMA VARIANTS

NODULAR SCLEROSIS CHD L DEPLETED CHD LYMPHOCYTE RICH CHD

11 ANN ARBOR STAGING WITH COTSWOLD MODIFICATION

12 STAGING STUDIES/PRE-TREATMENT STUDIES o PET CT o Labs: CBC, ESR, LFTs, albumin, BUN/Creat o PFTs (with DLCO) o Echo/MUGA o Fertility counseling as appropriate o HIV if risk factors present o Bone marrow asp/ no longer routinely recommended

13 INTERNATIONAL PROGNOSTIC SCORE FOR ADVANCED HD

. Age ≥45 years . Stage IV . Male sex . Leukocyte count ≥15,000 mm3 . Lymphocyte count <600 cells/mm3 or <8% . Albumin <4 g/dL . Hemoglobin <10.5 g/dL

14 TREATMENT OVERVIEW

. Standard therapy cures up to 80% . Early stage (I-IIa) can be treated with XRT, but now recommend 2-4 courses of followed by involved field radiation . Advanced stage always requires chemotherapy, 6-8 cycles – ABVD has replaced MOPP (less sterility and secondary ) – Patients with bulky disease(>10 cm should be consolidated with XRT) . Relapsed disease can be ‘salvaged’ with stem cell transplant +/- anti-CD30 monoclonal antibody (brentuximab vedotin) . Anti-PD1 immunotherapy is also very active in relapsed disease – Malignant cells in classical HL overexpress PD-1 ligands (highest of any tumor studied to date!)

15 HODGKIN’S LYMPHOMA

. Results of Treatment . stage 5 year overall survival – I 90% – II 90% – III 80% – IV 65%

16 LATE COMPLICATIONS

– Immunologic deficits/infections – Thyroid dysfunction (mainly after neck or mantle radiation) – Cardiac (Adriamycin)/pulmonary dysfunction (Bleomycin) – Gonadal dysfunction – Secondary malignancies – Hodgkin's lymphoma survivors who received extended-field radiation have a 1% risk/year for developing solid tumors. . Young women are particularly prone to developing breast cancer, with an actuarial lifetime risk for a patient treated with mediastinal of 50% to 60%.

17 NODULAR LYMPHOCYTE PREDOMINANT HD

Popcorn cell

18 NCCN RECOMMENDATIONS FOR NODULAR LPHL oStage IA or IIA disease o Radiation for all patients oStage 1B, IIB, III and IV o Chemotherapy + involved field XRT o Add Rituximab to chemotherapy (CD20+)

19 NON-HODGKIN’S OVERVIEW

. Non-Hodgkin’s Lymphomas (NHL) are a biologically and clinically heterogeneous group of malignant of lymphoid tissue. . B- cell lymphomas represent 80-85% . T-cell lymphomas represent 15-20% . NK- cell lymphomas are very rare . Approximately 70,000 new cases annually with 19,000 deaths . The incidence of NHL has increased markedly in the past 50 years, possibly due to: . Increased exposure to . Increased prevalence of immunosuppressed individuals

20 21 WORK UP

. Complete physical exam . Extra attention to node bearing areas and liver/ sizes . Lab studies . CBC, CMP, LDH, beta-2- microglobulin . Imaging . CT chest/abdomen/pelvis . Consider neck . PET CT . EUS gastric MALT . MRI and LP (Mantle cell, DLBCL and the highly aggressive lymphomas) . Excisional biopsy for morphology . FNA and core biopsy are usually inadequate . Bone Marrow biopsy

22 WORK-UP

. Immunophenotyping/Flow cytometry . Cytogenetics/ FISH . Molecular . Hepatitis B testing . HbsAg and Hbcore Ab . The use of Rituximab in patient with HbcAb positive has been reported to cause fatal HBV related liver disease . Anti-viral prophylaxis has been effective in preventing HepB reactivation during chemo-immunotherapy

23 NHL: INDOLENT LYMPHOMAS

. Typical scenario – patient presents with painless adenopathy – otherwise asymptomatic – follicular small cell histology – average age 59 – usually stage III-IV at diagnosis

24 INDOLENT NHL: WHEN TO TREAT?

. Guiding treatment principle . Early treatment does not prolong overall survival. – When to treat? . constitutional symptoms . compromise of a vital organ by compression or infiltration, particularly the bone marrow . bulky adenopathy (including massive splenomegaly) . rapid progression (or steady progression during >6 months of observation) . evidence of transformation . cytopenias

25 NON-HODGKIN’S LYMPHOMA

. Low-grade lymphoma – Grade 1 – Small cell (<5 large cells per HPF) – Grade 2 – Mixed cell (5-15 large cells per HPF) – Grade 3 – Large cell (>15 large cells per HPF) . Indolent in growth . Chemotherapy sensitive . Incurable . Cytogenetics: t(14;18)

26 FOLLICULAR LYMPHOMA

Mbr (major breakpoint region, 150 bp)

Bcl2 Chromosome 18

Cµ Chromosome 14

JH

Double strand DNA break by RAG1/2

Translocation takes place in B cell precursors.

Bcl2 Cµ t(14;18) translocation

Transformation takes place during B cell activation in GC.

bcl2 Eµ Cµ Cα 3’E Unregulation of Bcl2 expression by IgH enhancers

27 Bcl2 inhibits apoptosis Pro-survival

mitochondrion Bax, Bad

Pro-caspase-9 cytochrome c Bcl-2, Bcl-X L Apaf-1 dATP or ATP

Apaf-1 Caspase-9

Pro-caspase-3 Caspase-3

Apoptosis

28 Over-expression of Bcl-2 may prevent the apoptosis of germinal center B cells

Plasma cells

Germinal center Germinal center activation

apoptosis Memory cells

Germinal center Germinal center IgH-Bcl2

activation

Most follicular lymphoma Ig V regions contain follicular lymphoma somatic hypermutation. Apoptosis inhibited

29 TREATMENT

. Single agent Rituximab . Rituximab + Bendamustine (better than R-CHOP) . Rituximab maintenance (improved DFS not OS)

30 FOLLICULAR LYMPHOMA

. Histological Transformation to DLBCL . Occurs at an annual rate of 3% for 15 years, then rate decreases . Poor clinical outcome with median OS < 2 years . Pts with multiple prior therapies: . Enrollment in Clinical trial . Pt with minimal therapy (involved site radiation[ISRT] or 1 course of single chemo) or no chemotherapy . Anthracycline based regimen with Rituxan . Enrollment in clinical trial . Auto-SCT/ allogenic SCT

31 Diffuse Large B Cell NHL

Most common NHL (31%) Peak in 6th decade Slight male predominance (55%) 60% advanced at presentation 40% extra-nodal

32 DLBCL Clinical Presentation

Rapidly enlarging mass "B" symptoms 30 percent Increased serum LDH >50% stage III or IV disease 60% Localized disease 40% Bone marrow involvement up to 30% Extranodal, extramedullary disease up to 40%

33 Diffuse Large B Cell NHL Work-up

. PE with attention to node-bearing areas . Performance Status . B symptoms . CBC with diff, LDH, CMP, uric acid . CT chest/abd/pelvis and/or PET-CT . BM bx with aspirate . MUGA/Echo: if treatment with an anthracycline is indicated . Pregnancy testing . Hep B status – If treatment with Rituxan is indicated – Indicated due to risk of reactivation with immunotherapy + chemotherapy – Pt with no risk factors: check HepBsAg and HepBcAb – Pt with risk factors or previous history of hepatitis B: add HepBeAg – If positive: check viral load and consult with gastroenterologist

34 DLBCL Treatment

R-CHOP  Rituximab = anti-CD20 monoclonal antibody  Cyclophosphamide  Hydroxydaunorubicin = Doxorubicin  Oncovin = Vincristine  Prednisone (steroid)  Early stage disease without bulky nodes (<7.5 cm)  3 cycles followed by involved field radiation (IFRT) Advanced stage disease or early stage disease with bulky nodes  R-CHOP X 6 +/- IFRT  No benefit from maintenance Rituximab

35 INTERNATIONAL PROGNOSTIC INDEX

. Poor prognostic variables (Apples) CR and OS stratified by IPI – Age >60 years, Serum LDH > Normal, PS 2-4, Stage III or IV, # RF’s CR 5 yr OS Extra-nodal Involvement >1 site 0,1 87% 73% . Prognostic categories 2 67% 51% – Low 0-1; Low Intermediate 2; High Intermediate 3 ; High 4 or 5 3 55% 43% 4,5 44% 26%

36 NON-HODGKIN’S LYMPHOMA BURKITT’S NHL

. Very Aggressive . Highly curable with standard-dose therapy but requires very extensive chemotherapy protocol . Endemic (African) variant associated with EBV, but sporadic (Western) usually not . Translocation t(8,14) [variants t(2,8) and t(8,22)] . Ki67 100% . Specific Hematopathology Finding – Starry, Starry Night

37 Burkitt’s Lymphoma breakpoints

myc Chromosome 8

*** Cµ IgH Chromosome 14, 80% V(D)J Eµ Sµ Igκ Chromosome 2

Class switch recombination Igλ chromosome 22

Somatic hypermutation

3’E myc Cµ Cα Sµ t(8:14)

3’E myc Cµ Cα Eµ Sµ

38 Burkitt’s Lymphoma Starry, Starry Night

39 BL- TREATMENT OPTIONS

. Therapy must be initiated quickly because of the rapid clinical progression of the disease

. TLS precautions – Vigorous alkalinization, hydration, allopurinol, Rasburicase if needed, early dialysis at 1st sign of decreasing renal fcn

. Multiple studies have shown that CHOP chemotherapy is inadequate for BL

40 ACUTE MYELOGENOUS LEUKEMIA

41 ETIOLOGY / RISK FACTORS . Environment – benzene, ionizing radiation, smoking . Genetic Disorders – Down Syndrome – Bloom Syndrome – Fanconi Anemia – Ataxia-telangiectasia – Schwachman-Diamond syndrome – Li Fraumeni Syndrome . Pre-existing Hematologic disorders – MDS – MPN – PNH . Treatment-related – Chemotherapy / XRT

42 42 ALL CLL Lymphomas MM naïve

B-lymphocytes

Plasma Lymphoid cells progenitor T-lymphocytes

AML Myeloproliferative disorders

Hematopoietic Myeloid Neutrophils stem cell progenitor Eosinophils

Basophils

Monocytes

Platelets

Red cells

43 43 44 44 DIAGNOSING AML

• If your doctor suspects AML, more tests will be done, including: - Blood tests - Bone marrow tests - Biomarker testing, including: - Cytogenetics (chromosome tests) - FISH (fluorescence in situ hybridization) - Other molecular/genomic tests look for genetic mutations (changes) to the cancer cells such as FLT3, IDH1, IDH2, p53, NPM1, and CEBPA: - PCR (polymerase chain reaction) - DNA sequencing and microarray technologies - Next generation sequencing • Some of these tests may be repeated to measure how well treatment is working

45 46

Platelet Red Cell Blasts White Cell Platelet White Cell Red Cell

Normal human blood Blood with leukemia

46 DIAGNOSTIC EVALUATION

. > 20% blasts in peripheral blood or bone marrow (WHO) . Cytogenetic (irrespective of blast count) – t(8;21)(q22;q22) – inv(16)(p13q22) or t(16;16)(p13;q22) – t(15;17)(q22;q12) . Immunophenotype – HLA-DR – CD34 – CD13, CD33 . Morphology – Auer Rods

47 47 48 LYMPHOBLAST/MYELOBLAST

48 Gingival

49 49 CUTANEOUS MANIFESTATIONS

Leukemia cutis Sweet’s syndrome

50 50 WORKUP

• H & P • CBC w/ Differential • Peripheral Smear • Coagulation Studies - PT / PTT / TT/ Fibrinogen

51 51 PROGNOSIS IN AML parameters Favorable unfavorable Cytogenetics T(15;17). Deletion of T(8;21). chromosome 5 or 7. Inv(16). 11q23 (topoisomerase- related) T(6;9) 3q complex rearrangements FLT3 mutations BM response to <5% blasts after first >20% blasts after first remission induction course course.

Age <60yrs >60yrs

52 52 53 TREATMENT OPTIONS FOR AML

• The success of AML treatment depends on how well the first treatment goes. It is important to have your first treatments at a center and with a doctor experienced with treating AML • Usually, the first goal of treatment is to get the patient into complete remission • The long-term goal is to cure the disease • The main types of treatment for AML are: – Chemotherapy – main treatment – Targeted therapy – sometimes given along with chemo – Stem cell transplantation – which may follow chemo or be used with a 2nd phase of chemo – Clinical trials – to test new drugs, test combinations of drugs, or test different ways of doing stem cell transplant

53 TREATMENT

. Remission Induction – Chemotherapy . Post Remission Therapy – Chemotherapy (Consolidation) – HSCT . Goal = Complete Remission – ANC > 1,000 – Platelet > 100,000 – Blasts Count < 5%

54 54 STANDARD CHEMO - INDUCTION

Most AML patients are treated with a combination these drugs: • Cytarabine ‒ Cytosine arabinoside or ara-C (Cytosar-U®) • Anthracyclines ‒ Daunorubicin (Cerubidine®) ‒ Doxorubicin (Adriamycin® PFS, Adriamycin®) ‒ Idarubicin (Idamycin®) • Other drugs combinations may be used depending on your subtype of AML ‒ For example, Vyxeos® (daunorubicin and cytarabine liposome) is used in therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

55 TREATMENT >60 YO

. Poorer prognosis in older age – Comorbidities – Prior MDS – Poor Risk Cytogenetics – Multidrug resistance . Treatment options –Standard Induction –Vyxeos (a liposomal fixed combination of daunorubicin and cytarabine) – improved OS and less side-effects compared to standard induction for patients with therapy related leukemia and with MDS-related changes –Azacitidine

56 56 TARGETED THERAPY (RELAPSED/REFRACTORY)

If AML returns (relapses) or is still present after standard therapy (refractory):

• Enasidenib (Idhifa®) is used in IDH2+ AML • Ivosidenib (Tibsovo®) is used in IDH1+ AML • Gilteritinib (Xospata®) is used in FLT3+ AML • Gemtuzamab ozogamicin (MylotargTM) is used in CD33+ AML

57 TYPES OF TRANSPLANT

. Sibling vs. Matched unrelated donor . Matched vs. Haploidentical . Myeloablative vs. Non-myeloablative (mini-transplant)

58 58 ACUTE PROMYELOCYTIC LEUKEMIA (APL)

• 10-15% AML • Hispanic (20-25%) • Median Age 40 yo • Unique to AML because of its t(15;17) chromosomal translocation-fusion of PML gene on chromosome 15 with RAR alpha gene from chromosome 17 • Can occur as a result of cytotoxic therapy, especially with etoposide and doxorubicin

59 59 ATRA + ATO

Phase 3 multicenter trial comparing ATRA + ATO vs. ATRA +chemotherapy

CR achieved in all 77 patients in the ATRA + ATO group and in 75 of the 79 patients the ATRA + chemo group.

2-year event free survival-97% in ATO And 86% in chemo group

60 60 CHRONIC LYMPHOCYTIC LYMPHOMA

. CLL is a lymphoid . Characterized by progressive accumulation of functionally incompetent lymphocytes of monoclonal origin. . CLL is considered identical to the mature B-cell neoplasm small lymphocytic lymphoma (SLL) . CLL is disease manifestation in the bone marrow and blood . SLL is disease manifestation in the lymph nodes . The natural history is variable

61 ETIOLOGY OF CLL

. The exact etiology is uncertain . CLL has no known risk factors and not associated with radiation or chemical exposure . An increased familial incidence has been reported, though there is no clear genetic factors.

62 International Workshop on CLL criteria for diagnosis  Absolute B cell count in the peripheral blood >5000/µml for at least 3 months with preponderant morphologically mature appearing small lymphocytes  Demonstration of clonality - of the circulating B cells by flow cytometry with phenotype – low level of surface immunoglobulin, either kappa or lambda light Peripheral Smear : Increased number chain , CD5+, CD 19+, of mature mature, small to medium CD20+(dim), CD79b+ (dim) lymphocytes with the presence of classic smudge cells. REMEMBER : Bone marrow is not required for the diagnosis of CLL

63 PATHOPHYSIOLOGY

. CLL cells arise from polyclonal expansion of CD5+ B lymphocytes. . Transformed into a monoclonal population by mutational agents. . Neoplastic CD5+ cells accumulate in the lymph nodes and spleen due to the loss of apoptosis, by either 1. the over expression of an oncogene or 2. the loss of a .

64 CLINICAL PRESENTATION

. Most patients are asymptomatic at presentation. . 20% to 30% with lymphadenopathy . 40% to 50% with hepatosplenomegaly . Splenomegaly weight loss, recurrent infections, bleeding and signs/symptoms of anemia seen with advanced disease.

65 CLINICAL CLL STAGING

66 LABORATORY ABNORMALITIES

. Lymphocytosis — lymphocytosis in the peripheral blood and bone marrow. . Cytopenias — Neutropenia, anemia and thrombocytopenia . Autoimmune hemolytic anemia - in 20% to 30%, . Clinical hemolysis in 10% to 25% of pts . Hypogammaglobulinemia: in ~ 8% of pts.

67 DIAGNOSIS CRITERIA

. lymphocytosis of at least >= 5000/uL for 6 months or longer. . Peripheral blood: monomorphic, small, round B lymphocytes with a narrow border of cytoplasm and a dense nucleus. . Bone Marrow: >= 30% of lymphocytes . % of prolymphocytes less than 55% of lymphocytes . Immunophenotyping: abnormal B lymphocytes

 B cell surface antigens: CD19, CD23 as well as dim expression of CD20 and CD79b.  T cell surface antigen: CD5  Low monoclonal surface immunoglobulin with either κ or λ light chains (IgM or IgD).

68 PBS OF CLL

Smudge cells Lymphocytes w/ scant cytoplasm

69 CHROMOSOMAL ABNORMALITIES

. Döhner et al determined that chromosomal abnormalities may be identified in more than 80% of CLL cases. . These cytogenetic abnormalities can be identified by FISH analysis and . May be the most meaningful predictor of disease progression.

70 PROGNOSTIC FACTORS

. The Rai and Binet staging systems . Leukemic cell doubling time: LDT . Immunoglobulin heavy chain variable region gene: . 1. Mutated igHV gene . 2. Non-mutated igHV gene: trisomy 12 and > disease progression. . CD 38 +: must have > 30% of leukemic cell on FISH

71 PROGNOSTIC FACTORS, CONT.

. Zeta-associated protein of 70 kDA . 1. ZAP- 70 is a 70 kDA cytoplasmic protein tyrosine kinas originally expressed by T and natural killer cells . 2. Unmutated igHV genes express level of ZAP-70 compared to T cells. . 3. Mutated igHV genes do no express detectable levels ZAP 70 protein. . 4. CLL B cell with 20% or more leukemic cells with fluoresces intensity above a specified threshold. . 5. Patients have increase disease progression . 6. Strong predictor for need for early start of therapy in pts w/ + IgHV mutation . Study: 14/52

72 PROGNOSTIC FACTORS, CONT. . Cytogenetics: . Pts with multiple abnormalities + trisomy 12 has worse prognosis than trisomy 12 alone . Pts with trisomy 12 alone has worse prognosis than pts with normal karyotype . 4% and 10% noted to have 17q13 and 11q23 at diagnosis respectively. . Deletion 17q13 with defects in TP53 – associated with resistance to chemotherapy. . Pts refractory disease to chemo have CLL cells with 17q(23%) and 11q(27%) . Indication to repeat FISH before starting TX in pts who relapsed after initial therapy. . Finn et al. AMJ Hematol. 59:233, 1998

73 TREATMENT OF CLL

. Historically, the goal of treatment for CLL patients has been palliation of symptoms. . Asymptomatic early stage . Symptomatic or advanced stage . Patients with asymptomatic early stage (Rai stage <3, Binet stage A or B) CLL have a median survival > 10 years . Patients with advanced stage CLL or symptomatic disease have a median survival without treatment between 18 months and 3 years

74 WHY NOT TREAT CLL AT DIAGNOSIS

. Not all patients with CLL require treatment at the time of diagnosis . Indolent disease – certain subsets of patients having survival rates without treatment that are similar to the normal population . Cannot be cured by current treatment options w/ possible exception of allogeneic hematopoietic cell transplantation (HCT), . Prospective, randomized trials evaluating immediate versus delayed treatment strategies have found no improvement in long-term survival with early treatment

75 INDICATION FOR TREATMENT

Hemolytic anemia/thrombocytopenia poorly responsive to steroid

76 FIRST LINE THERAPY FOR SYMPTOMATIC CLL

. A choice of therapy is made based upon patient characteristics and goals of therapy . Age . Performance status . Prognostic factors: del 17p, del 11q

77 PROBABILITY OF SURVIVAL

78 78 SOME FDA APPROVED DRUG THERAPIES FOR CLL

Chemotherapy Targeted Therapy ● Bendamustine hydrochloride ● Ibrutinib (Imbruvica®) (BendekaTM) ● Idelalisib (Zydelig®) ● Chlorambucil (Leukeran®) ● Lenalidomide (Revlimid®) ● Cladribine (Leustatin®) ● Venetoclax (VenclextaTM) ● Cyclophosphamide (Cytoxan®) ● Doxorubicin (Adriamycin®) Monoclonal Antibody Therapy ● Fludarabine (Fludara®) ● Alemtuzumab (Campath®) ● Prednisone ● Obinutuzumab (Gazyva®) ● Ofatumumab (Arzerra®) ● Rituximab (Rituxan®)

79 79 CD20

. Activated glycosylated phosphoprotein expressed on all B- cells from the late pre-B to memory cell phases . Enables optimal B-cell immune response against T- cell independent antigens

. FDA-approved CD20-targeted agents: Rituximab Ofatumumab Obinutuzumab

80 80 TARGETING OF BCR SIGNALING IN CLL

. BCR-associated kinases are targets of new drugs in preclinical and clinical development

. BTK inhibitors: ibrutinib

. PI3 kinases: idelalisib

81 81 IBRUTINIB

Oral irreversible inhibitor that binds covalently to C481 of Bruton’s tyrosine kinase and prevents BCR signaling

1st-line 1st line FDA 2nd-line: with del in CLL: approval 2014 17p: 2016 2014

82 82 VENETOCLAX: MECHANISM OF ACTION

 FDA approval: April 11, 2016 chronic lymphocytic leukemia (CLL) with 17p deletion, who have received at least one prior therapy.

83 83 CD-19 TARGETED CHIMERIC ANTIGEN RECEPTOR (CAR) THERAPY

. Pt’s T cells are harvested . CAR directed against CD19 is introduced into these T cells . These T cells are expanded ex vivo (for 2 wks),and then infused

84 84 CD19 CAR THERAPY

. CD19 is almost exclusively expressed in malignant and normal B- cells, hence is a good target for CAR therapy in B- cell malignancies . In 14 R/R-CLL pts, ORR 57% (4 CRs) . AEs: delayed cytokine release (CRS) syndrome, B-cell aplasia, hypogammaglobulinemia . CRS treatment: tocilizumab (IL-6 inhibitor), steroids

Kalos et al. Blood. 2013. 85 85